Project 4 is an integral component of the Dartmouth Superfund Basic Research Program (SBRP), focusing on the environmental and health impact of toxic metal exposure in the US. We propose to build on 12 years of experience designing and testing methods of measuring environmentally relevant levels of exposure and factors that influence individual susceptibility to metal-related health effects. Accumulating data point to the developing fetus as particularly vulnerable to environmental insults and that early life exposures impact childhood and adult health. Thus, we propose to test the hypothesis that prenatal exposure to arsenic is associated with birth outcomes (e.g., birth weight, fetal growth restriction and gestational age) in the New Hampshire population. We also will assess whether individual variation in arsenic metabolism (based on maternal urinary metabolites, arsenic metabolism genes e.g., GSTO1, GSTO2, AS3T, PNP) and other factors (e.g., smoking, folate or polymorphisms in one carbon metabolism genes) modify these effects. We will evaluate the reliability of multiple measures of metal exposure (e.g., in drinking water, hair, nails and urine) within mothers and in mother-infant pairs. Secondarily, we will investigate the hypothesis that methylmercury intake alone or in combination with other factors influences fetal growth and gestational age. We will conduct a collaborative analysis with the NIEHS-funded New Bedford birth cohort study (adjacent to a Superfund Site) to increase statistical power. Programatically, we will: (1) test innovative strategies for the detection, characterization and interpretation of gene-environment interactions (with the Integrative Biology Core (IBC)), (2) explore dietary sources and geographic patterns of metal exposure (with Projects 7, 9), (3) provide a platform for translational molecular, genetic, and proteomic studies (for the IBC, Projects 2, 7, 8, 9) and (4) investigate the functional effects of polymorphisms in metal transporter genes (with the IBC, Projects 8, 9). We will expand collaborative and translational activities with other SBRPs, universities and agencies. To our knowledge, the study proposed will represent among the first molecular epidemiologic investigations of early life exposure to arsenic and mercury in a general population of the US. Our goal is to inform risk assessment and management of toxic metal exposure in the US, and aid early intervention strategies to prevent adverse health effects from these exposures.